Carbidopa-Levodopa

Aka: Carbidopa-Levodopa, Carbidopa Levodopa, Levodopa, Carbidopa/Levodopa, Levodopa-Carbidopa, Levodopa/Carbidopa, Sinemet, Stalevo, Dopa decarboxylase inhibitor, Dopamine Precursor, Rytary, Duopa, Inbrija

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II. Indications

  1. Parkinsonism
  2. Restless Leg Syndrome (off-label)
  3. Dopa Responsive Dystonia (off-label)

III. Mechanism

  1. Levodopa is decarboxylated to Dopamine in the Central Nervous System (CNS)
    1. Dopamine is unable to cross the blood brain barrier
  2. Levodopa is combined with carbidopa, a peripheral decarboxylase inhibitor
    1. Carbidopa blocks the peripheral decarboxylation of Levodopa
    2. Without carbidopa, 99% of Levodopa would undergo peripheral decarboxylation and fail to reach the CNS
    3. Carbidopa also reduces peripheral Dopamine adverse effects (e.g. Orthostatic Hypotension, Nausea, Vomiting)

IV. Pharmacokinetics

  1. Rapidly absorbed orally
  2. Half-Life (non-sustained release): 1 to 3 hours

V. Precautions: General pointers

  1. Levodopa/Carbidopa (Sinemet, regular release) is by far the single most effective agent in Parkinsonism
    1. This agent should be the first line and main agent used for Parkinsonism
    2. All other agents are adjuncts only
  2. Dosing Threshold
    1. Identify the individual patient's optimal dose and use this dose at each dosing interval
    2. Using a lower dose below threshold will be inadequate
  3. Food Interactions
    1. Take at least one hour before a meal or 2 hours after a meal
    2. Levodopa is absorbed in the Small Intestine and impacted by gastric emptying
    3. However, patients may wish to initially take with food to reduce Nausea, and then space from food intake
  4. Wearing off of effect
    1. See frequency of dosing of Sinemet below
    2. Most common cause of Insomnia
    3. May cause anxiety, nocturnal cramps
    4. Duration of activity decreases with longterm use
      1. First 2 to 5 years of use: Consistent 5-6 hours of effect
      2. After 5-8 years: Motor fluctuations, Dyskinesia (on-off effect impacting mobility)
      3. Longterm: Progressive disorders of balance, gait, speech, Swallowing
  5. Dyskinesia (e.g. Choreiform movements)
    1. Dyskinesia is more age related than that of duration of Levodopa use
    2. Reducing each Levodopa dose decreases this adverse effect
    3. Amantadine decreases Dyskinesia
  6. Adverse Effects: Educate patients about serious effects (most are reduced by tapering dose)
    1. Drowsiness
    2. Pathologic Gambling, Hypersexuality, Excessive shopping/spending
    3. Hallucinations or Delusions
    4. Swelling

VI. Medications

  1. Carbidopa/Levodopa (Sinemet, Immediate Release)
    1. IR Tablet (Sinemet): 10/100 mg, 25/100 mg, 25/250 mg
    2. IR ODT Tablet (Parcopa): 10/100 mg, 25/100 mg, 25/250 mg
    3. Triple Scored IR Tablet (Dhivy)
      1. One tablet (25/100 mg) may be divided 1/4 (6.25/100), 1/2 (12.5/50) or 3/4 (18.75/75)
  2. Carbidopa/Levodopa Controlled Release (Sinemet CR)
    1. ER Tablet: 25/100 mg, 50/200 mg
  3. Carbidopa/Levodopa fast onset, sustained release (Rytary)
    1. IR/ER Capsule: 23.75/95 mg, 36.25/145 mg, 48.75/195 mg, 61.25/245 mg
    2. Capsules may be opened and contents sprinkled on food
  4. Carbidopa/Levodopa Biphasic Extended Release (Crexont)
    1. Biphasic ER Capsule: 35/140 mg, 52.5/210 mg, 70/280 mg, 87.5/350 mg
    2. Do not open biphasic capsule
  5. Carbidopa/Levodopa/Entacapone (Stalevo)
    1. Entacapone 200 mg combined with Immediate Release Carbidopa 12.5 to 50 mg, Levodopa 50 to 200 mg
  6. Carbidopa/Levodopa Enteral Suspension (Duopa)
  7. Inbrija (inhaled Levodopa)

VII. Dosing: Parkinsonism

  1. Carbidopa/Levodopa (Sinemet, Immediate Release)
    1. Preferred option over sustained release (first-line agent)
      1. Lower cost
      2. Better Pharmacokinetics
      3. Less Drug Interactions
    2. Dosing
      1. Start at 25 mg/100 mg (or 10 mg/100 mg) orally three times daily
      2. Increase by on half to one tablet every 1-2 days as needed
      3. Maximum : 3 tablets per dose, three times daily (no benefit to higher doses, but frequency may be increased)
    3. Frequency of dose
      1. Initially give dose three times daily
      2. Long term, dose may wear off early
        1. Frequency may need to be increased to every 6 hours (at same number of tablets at each dose)
    4. Emergency Dosing (rescue dose for hypomobility, "off" episode)
      1. Crushed Carbidopa/Levodopa tablets may be dissolved in carbonated beverage
  2. Carbidopa/Levodopa Controlled Release (Sinemet CR)
    1. Start at 50/200 orally twice daily
      1. Convert 300-400 mg Levodopa immediate release/day to start CR 200 mg Levodopa twice daily
      2. Convert 500-600 mg Levodopa immediate release/day to start CR 300 mg Levodopa twice daily
      3. Convert 700-800 mg Levodopa immediate release/day to start CR 800 mg/day Levodopa divided three times daily
      4. Convert 900-1000 mg Levodopa immediate release/day to start CR 1000 mg/day Levodopa divided three times daily
    2. Increase by one tablet every 3 days as needed
    3. Maximum : 8 tablets daily
    4. No benefit over immediate release in motor function, and absorption may be sporadic in some patients
  3. Carbidopa/Levodopa fast onset, sustained release (Rytary)
    1. Start with lowest dose 23.75/95 mg orally three times daily
      1. May increase to 36.25/145 mg orally three times daily after 3 or more days
    2. Typical Dose: 3-4 caps three times daily
    3. Maximum: 97.5 mg/390 mg three times daily
    4. Onset within 1 hour, duration of 6 hours
    5. Costs 3-4 times more than generic Carbidopa/Levodopa
    6. May decrease "off time", the wearing off of activity between doses
    7. Consider in advanced Parkinsonism for "off time" problems despite four time daily dosing
    8. Requires higher dosing than other preparations due to lower Bioavailability
    9. (2015) Presc Lett 22(7): 41
  4. Carbidopa/Levodopa/Entacapone (Stalevo)
    1. Start at 12.5/50/200 orally twice daily
    2. Increase slowly
    3. Maximum : 8 tablets daily
  5. Carbidopa/Levodopa Enteral Suspension (Duopa)
    1. Consider for refractory on-off effects with oral dosing (suspension may have more consistent absorption and sustained effects)
    2. Convert from immediate release dosing to administer over 16 hours (max daily dose 2000 mg)
    3. Enteral suspension delivered via GJ-Tube with portable infusion pump over 16 hours
    4. Consider following infusion with a nighttime oral immediate release dose
  6. Inbrija (inhaled Levodopa)
    1. Indicated in off-time motor rigidity or Tremor
    2. Rapid onset (10 min after inhalation) and duration of 1 hour used for prn "off time" rigidity or Tremor
    3. Less expensive ($30/dose) than Apokyn ($200/dose), an injectable option for off-time
    4. Requires dexterity to replace capsule in Inhaler
    5. Avoid in underlying lung disease (e.g. Asthma, COPD) due to bronchospasm risk
    6. (2019) Presc Lett 26(5)

VIII. Dosing: Non-Parkinsonism Indications

  1. Restless Leg Syndrome
    1. Start Carbidopa/Levodopa (Immediate Release) 1/2 of a 25 mg/100 mg orally at bedtime
    2. Titrate to effect increasing by 1/2 tablet every 3-4 days to a maximum of 2 tablets (50 mg/200 mg) at bedtime
    3. May use a combination of immediate release and controlled release Carbidopa/Levodopa if symptomatic night awakenings
  2. Dopa Responsive Dystonia
    1. Start Carbidopa/Levodopa (Immediate Release) 25 mg/100 mg tablet orally daily
    2. Titrate to effect (maximum Levodopa 1000 mg/day)

IX. Adverse Effects

  1. Nausea
  2. Somnolence
  3. Hallucinations
  4. Dizziness or Orthostasis
  5. Delusions
  6. Dyskinesias
  7. Lower Extremity Edema
  8. Major Depression and Suicidal Ideation
  9. Compulsive Gambling (or sexual activity)

X. Drug Interactions

  1. Pyridoxine
    1. Stimulates decarboxylation (may prevent Levodopa from reaching CNS)
  2. Antipsychotic agents
    1. Block Dopamine receptors
  3. MAO Inhibitors
    1. MAO Inhibitors increase Sympathomimetic amine accumulation
    2. Stop non-selective MAO Inhibitors at least 2 weeks prior to Levodopa start
  4. Anticholinergic Agents
    1. Anticholinergic Agents slow gastric emptying, delay absorption, but may increase overall Levodopa levels

XI. Safety

  1. Pregnancy Category C
  2. Avoid in Lactation

XII. Efficacy

  1. Carbidopa-Levodopa is the most effective of the Parkinsonism agents for Tremor, rigidity and slow movement

XIII. Resources

  1. Levodopa/Carbidopa (Dailymed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a7b37778-d198-4799-8bf0-92576cff02b9

XIV. References

  1. (2025) Presc Lett 32(1):3-4
  2. (2021) Med Lett Drugs Ther 63(1618): 25-32
  3. Ahlskog (2011) Mayo Internal Medicine Review Lecture
  4. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  5. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 46-7
  6. Schim (2001) CMEA Medicine Lecture, San Diego
  7. Clarke (2003) Clin Evid 10:1582-98 [PubMed]
  8. Clarke (2004) Lancet Neurol 3:466-74 [PubMed]
  9. Gazewood (2013) Am Fam Physician 87(4): 267-73 [PubMed]
  10. Halli-Tierney (2020) Am Fam Physician 102(11):679-91 [PubMed]
  11. Nutt (2005) N Engl J Med 353:1021-7 [PubMed]
  12. Olanow (2001) Neurology 56:S1-88 [PubMed]
  13. Rao (2006) Am Fam Physician 74:2046-56 [PubMed]
  14. Young (1999) Am Fam Physician 59(8):2155-67 [PubMed]

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Related Studies

Cost: Medications

carbidopa-levodopa (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
CARBIDOPA-LEVODOPA 10-100 TAB Generic $0.14 each
CARBIDOPA-LEVODOPA 25-100 TAB Generic $0.11 each
CARBIDOPA-LEVODOPA 25-250 TAB Generic $0.14 each
CARBIDOPA-LEVODOPA-ENTACAPONE 25-100-200 MG TAB Generic $0.73 each
CARBIDOPA-LEVODOPA-ENTACAPONE 31.25-125-200 MG TAB Generic $1.05 each
CARBIDOPA-LEVODOPA-ENTACAPONE 37.5-150-200 MG TAB Generic $0.80 each
CARBIDOPA-LEVODOPA-ENTACAPONE 50-200-200 MG TAB Generic $0.92 each
rytary (on 7/20/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
RYTARY ER 23.75 MG-95 MG CAP $3.70 each
RYTARY ER 36.25 MG-145 MG CAP $3.70 each
RYTARY ER 48.75 MG-195 MG CAP $3.74 each
RYTARY ER 61.25 MG-245 MG CAP $4.61 each
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information. GoodRx is another tool for finding lower drug prices.

Ontology: Levodopa (C0023570)

Definition (NCI) An amino acid precursor of dopamine with antiparkinsonian properties. Levodopa is a prodrug that is converted to dopamine by DOPA decarboxylase and can cross the blood-brain barrier. When in the brain, levodopa is decarboxylated to dopamine and stimulates the dopaminergic receptors, thereby compensating for the depleted supply of endogenous dopamine seen in Parkinson's disease. To assure that adequate concentrations of levodopa reach the central nervous system, it is administered with carbidopa, a decarboxylase inhibitor that does not cross the blood-brain barrier, thereby diminishing the decarboxylation and inactivation of levodopa in peripheral tissues and increasing the delivery of dopamine to the CNS.
Definition (MSH) The naturally occurring form of DIHYDROXYPHENYLALANINE and the immediate precursor of DOPAMINE. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to DOPAMINE. It is used for the treatment of PARKINSONIAN DISORDERS and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system.
Definition (CSP) naturally occuring form of DOPA and precursor of dopamine; used as an antiparkinsonian agent; unlike dopamine it can be administered orally.
Definition (PDQ) An amino acid precursor of dopamine with antiparkinsonian properties. Levodopa is a prodrug that is converted to dopamine by DOPA decarboxylase and can cross the blood-brain barrier. When in the brain, levodopa is decarboxylated to dopamine and stimulates the dopaminergic receptors, thereby compensating for the depleted supply of endogenous dopamine seen in Parkinson's disease. To assure that adequate concentrations of levodopa reach the central nervous system, it is administered with carbidopa, a decarboxylase inhibitor that does not cross the blood-brain barrier, thereby diminishing the decarboxylation and inactivation of levodopa in peripheral tissues and increasing the delivery of dopamine to the CNS. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42622&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42622&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C611" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Neuroreactive Substance or Biogenic Amine (T124) , Amino Acid, Peptide, or Protein (T116)
MSH D007980
SnomedCT 15383004, 387086006, 65955006
LNC LP32555-2, LP16328-4, MTHU015998
English L-3,4-Dihydroxyphenylalanine, L-Dopa, Levodopa, 3 Hydroxy L tyrosine, 3-Hydroxy-L-tyrosine, L 3,4 Dihydroxyphenylalanine, (--)-3-(3,4-Dihydroxyphenyl)-L-alanine, beta-(3,4-Dihydroxyphenyl)-L-alanine, (--)-2Amino-3-)3,4-dihydroxyphenyl)propanoic Acid, DOPA A L, levodopa, LEVODOPA, Levodopa [Chemical/Ingredient], l-dopa, l dopa levodopa, dopa l, l dopa, L 3,4-dihydroxyphenylalanine, (--)-2Amino-3-(3,4-dihydroxyphenyl)propanoic Acid, L-DOPA, .beta.-(3,4-Dihydroxyphenyl)-L-alanine, L-.beta.-(3,4-Dihydroxyphenyl)alanine, (-)-3-(3,4-Dihydroxyphenyl)-L-alanine, L(-)-Dopa, 3-(3,4-Dihydroxyphenyl)-L-alanine, L-dopa, L-3-hydroxytyrosine, L-Dopa - Levodopa, L-dopa preparation, Levodopa (product), Levodopa (substance), L Dopa
Swedish Levodopa
Czech levodopa
Spanish L-dopa, L-3-hidroxitirosina, levo-dopa, levodopa (producto), levodopa (sustancia), levodopa, preparado de L-dopa, L-Dopa, Levodopa
Finnish Levodopa
Russian LEVODOFA, LEVODOPA, L-DOFA, L-DOPA, L-ДОФА, ЛЕВОДОПА, ЛЕВОДОФА
French 3-Hydroxy-L-tyrosine, L-Dopa, Lévodopa
German DOPA A L, L-Dopa, Levodopa
Croatian LEVODOPA
Polish Lewodopa, L-dopa
Japanese L-ジオキシフェニルアラニン, L-ドーパ, ドパストン, ドパール, レボドパ, レボドーパ, Lド-パ, Lドパ
Italian Levodopa
Portuguese L-Dopa, Levodopa
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Sinemet (C0074559)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C009265
English Sinemet, BMS brand of carbidopa, levodopa drug combination, sinemet
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Carbidopa / Levodopa (C0353697)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
SnomedCT 323113004, 372605005, 346377002, 404830004
English Levodopa with carbidopa, CARBIDOPA/LEVODOPA, carbidopa + levodopa, carbidopa + levodopa (medication), Carbidopa-Levodopa, carbidopa-levodopa, Carbidopa / Levodopa, levodopa carbidopa, carbidopa levodopa, co careldopa, co-careldopa, levodopa with carbidopa, Levodopa with carbidopa (product), Co-careldopa (substance), Co-careldopa (product), Carbidopa+levodopa (product), Carbidopa+levodopa, Levodopa with carbidopa (substance), Carbidopa and Levodopa, Co-careldopa
Spanish levodopa con carbidopa, co-careldopa (producto), levodopa-carbidopa, levodopa-carbidopa (sustancia), levodopa con carbidopa (producto), co-careldopa, co-careldopa (sustancia), carbidopa + levodopa (producto), carbidopa + levodopa
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Carbidopa / entacapone / Levodopa (C1329991)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
SnomedCT 410860008
English CARBIDOPA/LEVODOPA/ENTACAPONE @ @ UNIDENTIFIED, CARBIDOPA/LEVODOPA/ENTACAPONE UNIDENTIFIED, CARBIDOPA/ENTACAPONE/LEVODOPA, carbidopa + levodopa + entacapone, carbidopa + levodopa + entacapone (medication), Carbidopa / entacapone / Levodopa, Carbidopa/Entacapone/Levodopa, carbidopa/entacapone/levodopa, Carbidopa+levodopa+entacapone (product), Carbidopa+levodopa+entacapone, Levodopa+careldopa+entacapone
Spanish carbidopa+levodopa+entacapona (producto), carbidopa+levodopa+entacapona
Derived from the NIH UMLS (Unified Medical Language System)

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